Transmucosal phosphodiesterase inhibitors for the treatment of erectile dysfunction

ABSTRACT

A pharmaceutical formulation is provided for treating erectile dysfunction in a mammalian male individual. The pharmaceutical formulation includes a phosphodiesterase inhibitor or a pharmaceutically acceptable salt, ester, amide or derivative thereof, that is administered transmucosally within the context of an effective dosing regimen. Preferred modes of administration include transbuccal, sublingual and transrectal routes. A kit for the administration of the pharmaceutical formulation is also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional application of U.S. Ser. No.09/467,094, filed Dec. 10, 1999, which is a continuation-in-part of U.S.Ser. No. 09/181,070, filed Oct. 27, 1998, which is acontinuation-in-part of U.S. Ser. No. 08/958,816, filed Oct. 28, 1997,the disclosures of which are hereby incorporated by reference.

TECHNICAL FIELD

[0002] This invention relates generally to methods and pharmaceuticalcompositions for treating erectile dysfunction; more particularly, theinvention relates to transmucosal (e.g., buccal, sublingual andtransrectal), phosphodiesterase inhibitors that are used to treaterectile dysfunction.

BACKGROUND

[0003] Impotence is the consistent inability to achieve or sustain anerection of sufficient rigidity for sexual intercourse. It has recentlybeen estimated that approximately 10 million American men are impotent(R. Shabsigh et al., “Evaluation of Erectile Impotence,” Urology32:83-90 (1988); W. L. Furlow, “Prevalence of Impotence in the UnitedStates,” Med. Aspects Hum. Sex. 19:13-6 (1985)). Impotence is recognizedto be an age-dependent disorder, with an incidence of 1.9 percent at 40years of age and 25 percent at 65 years of age (A. C. Kinsey et al.,“Age and Sexual Outlet,” in Sexual Behavior in the Human Male; A. C.Kinsey et al., eds., Philadelphia, Pa.: W. B. Saunders, 218-262 (1948)).In 1985 in the United States, impotence accounted for more than severalhundred thousand outpatient visits to physicians (National Center forHealth Statistics, National Hospital Discharge Survey, 1985, Bethesda,Md., Department of Health and Human Services, 1989 DHHS publication no.87-1751). Depending on the nature and cause of the problem, treatmentsinclude psychosexual therapy, hormonal therapy, administration ofvasodilators such as nitroglycerin and -adrenergic blocking agents(“-blockers”), oral administration of other pharmaceutical agents,vascular surgery, implanted penile prostheses, vacuum constrictiondevices and external aids such as penile splints to support the penis orpenile constricting rings to alter the flow of blood through the penis.

[0004] A number of causes of impotence have been identified, includingvasculogenic, neurogenic, endocrinologic and psychogenic. Vasculogenicimpotence, which is caused by alterations in the flow of blood to andfrom the penis, is thought to be the most frequent organic cause ofimpotence. Common risk factors for vasculogenic impotence includehypertension, diabetes, cigarette smoking, pelvic trauma, and the like.Neurogenic impotence is associated with spinal-cord injury, multiplesclerosis, peripheral neuropathy caused by diabetes or alcoholism andseverance of the autonomic nerve supply to the penis consequent toprostate surgery. Erectile dysfunction is also associated withdisturbances in endocrine function resulting in low circulatingtestosterone levels and elevated prolactin levels.

[0005] Impotence can also be a side effect of various classes of drugs,in particular, those that interfere with central neuroendocrine controlor local neurovascular control of penile smooth muscle. Krane et al.,New England Journal of Medicine 321:1648 (1989). Penile erectionrequires (I) dilation of the arteries that regulate blood flow to thelacunae of the corpora cavernosum, (2) relaxation of trabecular smoothmuscle, which facilitates engorgement of the penis with blood, and (3)compression of the venules by the expanding trabecular walls to decreasevenous outflow.

[0006] Trabecular smooth muscle tone is controlled locally by adrenergic(constrictor), cholinergic (dilator) and nonadrenergic, noncholinergic(dilator) innervation, and by endothelium-derived vasoactive substancessuch as vasoactive intestinal polypeptide (VIP), prostanoids, endothelinand nitric oxide. High sympathetic tone (noradrenergic) is implicated inerectile dysfunction, and, in some patients, the disorder can besuccessfully treated with noradrenergic receptor antagonists. See, e.g.,Krane et al., supra.

[0007] There is also evidence that dopaminergic mechanisms are involvedin erectile function. For example, pharmacologic agents that elevate thelevel of brain dopamine or stimulate brain dopamine receptors increasesexual activity in animals (see, e.g., Gessa & Tagliamonte, LifeSciences 14:425 (1974); Da Prada et al., Brain Research 57:383 (1973)).

[0008] Administration of L-DOPA, a dopamine precursor, enhances sexualactivity in male rats. L-DOPA has been used in the treatment ofParkinsonism and is known to act as an aphrodisiac in some patients(Gessa & Tagliamonte, supra; Hyppa et al., Acta Neurologic Scand. 46:223(Supp. 43, 1970)). Specific dopamine agonists have been studied fortheir effects on erectile function. Apomorphine,(n-propyl)norapo-morphine, bromocryptine, amantidine, fenfluramine,L-DOPA and various other pharmacological activators of centraldopaminergic receptors have been found to increase episodes of penileerection in male rats (Benassi-Benelli et al., Arch. int. Pharmacodyn.242:241 (1979); Poggioli et al., Riv. di Farm. & Terap. 9:213 (1978);Falaschi et al., Apomorphine and Other Dopaminomimetics, 1: 117-121(Gessa & Corsini, Eds., Raven Press, N.Y.)). In addition, U.S. Pat. No.4,521,421 to Foreman relates to the oral or intravenous administrationof quinoline compounds to treat sexual dysfunction in mammals.

[0009] The currently available dopamine agonists, with few exceptions,have found limited use in the treatment of erectile dysfunction becauseof their peripheral side effects. These effects include nausea andvomiting, postural hypotension, arrhythmias, tachycardia, dysphoria,psychosis, hallucinations, drowsiness and dyskinesias (See, e.g.,Martindale The Extra Pharmacopoeia, 31 st Ed., pages 1151-1168).

[0010] The invention described herein provides a means to avoid theabove-mentioned problems encountered with previously known methods fortreating erectile dysfunction. Specifically, the invention relates tomethods and formulations for effectively treating erectile dysfunctionby transmucosally, e.g., buccally, sublingually or transrectally,administering a selected active agent, wherein the active agent is aninhibitor of a phosphodiesterase.

[0011] Phosphodiesterases are a class of intracellular enzymes involvedin the metabolism of the second messenger nucleotides, cyclic adenosinemonophosphate (cAMP), and cyclic guanosine monophosphate (cGMP) (see,e.g., Doherty, “Oral, Transdermal, and Transurethral Therapies forErectile Dysfunction” in Male Infertility and Dysfunction, Hellstrom,ed., Chapter 34 (New York, N.Y.: Springer-VerlagHellstrom, 1997)).Numerous phosphodiesterase inhibitors have previously been described inthe literature for a variety of therapeutic uses, including treatment ofobstructive lung disease, allergies, hypertension, angina, congestiveheart failure and depression (see, e.g., Goodman and Gilman's ThePharmacological Basis of Therapeutics Ninth Edition, Chapter 34). Oraland parenteral administration of phosphodiesterase inhibitors, asalluded to above, have also been suggested for the treatment of erectiledysfunction (Doherty, supra; see also PCT Publication Nos. WO 96/16644,and WO 94/28902). The phosphodiesterases have been classified into sevenmajor families, Types I-VII, based on amino acid or DNA sequences. Themembers of the family vary in their tissue, cellular and subcellulardistribution, as well as their links to cAMP and cGMP pathways. Forexample, the corpora cavernosa contains: Type III phosphodiesterases,which are cAMP-specific cGMP inhibitable; Type IV phosphodiesterases,the high affinity, high-specificity cAMP-specific form; and Type Vphosphodiesterases, one of the cGMP-specific forms.

[0012] The invention, as noted above, is directed to transmucosaladministration of pharmacologically active agents to treat erectiledysfunction. The agents are preferably, although not necessarily, TypeIII, Type IV or Type V phosphodiesterase inhibitors. Surprisingly, ithas now been found by the inventors herein that transmucosal andparticularly buccal, sublingual or transrectal administration of thesephosphodiesterase inhibitors as disclosed herein is highly effective intreating erectile dysfunction, including vasculogenic impotence.Transmucosal and particularly buccal, sublingual or transrectaladministration of phosphodiesterase inhibitors to treat erectiledysfunction accordingly represents an important advance in the treatmentof impotence and other erectile disorders.

SUMMARY OF THE INVENTION

[0013] It is a primary object of the invention to provide pharmaceuticalformulations for treating erectile dysfunction that have atherapeutically effective amount of a selected phosphodiesteraseinhibitor and that are administered transmucosally.

[0014] It is another object of the invention to provide thepharmaceutical formulation for transbuccal administration.

[0015] It is a further object of the invention to provide thepharmaceutical formulation for application to the sublingual mucosa.

[0016] It is still another object of the invention to provide thepharmaceutical formulation for application to the rectal mucosa.

[0017] It is another object of the invention to provide thepharmaceutical formulation with a Type III phosphodiesterase inhibitor.

[0018] It is a further object of the invention to provide thepharmaceutical formulation with a Type IV phosphodiesterase inhibitor.

[0019] It is yet another object of the invention to provide thepharmaceutical formulation with a Type V phosphodiesterase inhibitor.

[0020] It is yet another object of the invention to provide a kitcapable of use by an individual for self-administration of aphosphodiesterase inhibitor as provided herein.

[0021] Additional objects, advantages and novel features of theinvention will be set forth in part in the description that follows, andin part will become apparent to those skilled in the art uponexamination of the following, or may be learned by practice of theinvention.

[0022] In one aspect of the invention, a method is provided for treatingan individual prone to erectile dysfunction, e.g., vasculogenic erectiledysfunction, the method comprising transmucosally administering to theindividual a pharmaceutical formulation containing a phosphodiesteraseinhibitor. Administration of the pharmaceutical formulation is carriedout within the context of a predetermined dosing regimen such that theagent is effective in the treatment of erectile dysfunction. The methodis especially useful in the treatment of vasculogenic impotence,although other types of erectile dysfunction may also be treated usingthe present formulations, e.g., neurogenic, endocrinologic andpsychogenic impotence. Drug delivery is preferably effected through thebuccal mucosa, sublingual mucosa or transrectal mucosa but the drug mayalso be administered through other mucosal surfaces of the body. Forbuccal administration, the active agent is typically although notnecessarily administered by affixing a buccal dosage unit to the buccalmucosa of the individual undergoing treatment, and allowing the dosageunit to remain in place until drug delivery is complete. Alternatively,buccal administration may be effected by the application to the buccalmucosa of a cream, ointment or paste containing the active agent. Forsublingual administration, the active agent is typically although notnecessarily administered by placing a sublingual tablet under the tongueof the individual undergoing treatment, and allowing the tablet toremain in place until tablet disintegration and thus drug delivery iscomplete. For transrectal administration, the active agent is typicallyalthough not necessarily administered by placing a suppository withinthe rectum and allowing the dosage unit to remain in place until meltingof the carrier and thus drug delivery is complete. Alternatively,transrectal administration may be effected using a cream, ointment orsolution (e.g., enema) containing the active agent.

[0023] In another aspect of the invention, a pharmaceutical formulationis provided for carrying out the present method for treating erectiledysfunction. The pharmaceutical formulation comprises an effectiveamount of a phosphodiesterase inhibitor, a carrier or vehicle suited totransmucosal administration and, optionally, a permeation enhancer. Theformulation may contain one or more additional active agents, e.g.,dopaminergic drugs, smooth muscle relaxants, vasoactive drugs, andadditives, e.g., excipients, surfactants, preservatives (e.g.,antioxidants), stabilizers, chelating agents, enzyme inhibitors,antibacterial agents, binders, diluents, lubricants, and the like, aswill be appreciated by those skilled in the art of drug formulationpreparation and delivery. Buccal formulations will generally althoughnot necessarily comprise a solid dosage unit containing the activeagent, a hydrolyzable (or “bioerodible”) polymeric carrier, and a meansfor affixing the dosage unit to the buccal mucosa. The latter mayrepresent a separate adhesive component in the formulation, or thepolymeric carrier itself may serve as an adhesive. Sublingualformulations comprise a dosage form for application to the sublingualmucosa and a carrier suitable for sublingual drug delivery. Thus,sublingual formulations will generally although not necessarily comprisea solid dosage unit containing the active agent and one or more vehiclesand a lubricant. Transrectal formulations comprise a dosage form forapplication to the rectal mucosa and a carrier suitable for transrectaldrug delivery. Thus, transrectal formulations in the form of asuppository will generally although not necessarily comprise a soliddosage unit containing the active agent and one or more suppositorybases.

[0024] In another aspect, a kit is provided to assist an individual indrug administration to carry out the method of the invention. Generally,the kit will include the following components: a pharmaceuticalformulation comprising the phosphodiesterase inhibitor to beadministered; a container housing the pharmaceutical formulation duringstorage and prior to use; and instructions for carrying out drugadministration in a manner effective to treat erectile dysfunction. Whenthe kit is for assisting an individual in buccal drug administration,specifically, the kit will include at least the following: a buccaldosage unit comprising the active agent and a bioerodible polymericcarrier; a container housing the dosage unit prior to use; and writteninstructions for carrying out administration of the active agent for theintended therapeutic purpose.

DETAILED DESCRIPTION OF THE INVENTION

[0025] Definitions:

[0026] Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particular drugs ordrug delivery systems, as such may vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting.

[0027] It must be noted that, as used in this specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “a phosphodiesterase inhibitor” includes a mixtureof two or more such compounds, reference to “a permeation enhancer”includes mixtures of two or more enhancers, and the like.

[0028] In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set outbelow.

[0029] The term “erectile dysfunction” is intended to include any andall types of erectile dysfunction, including: vasculogenic, neurogenic,endocrinologic and psychogenic impotence (“impotence” is used here inits broadest sense to indicate a periodic or consistent inability toachieve or sustain an erection of sufficient rigidity for sexualintercourse; see U.S. Pat. No. 5,242,391 to Place et al., cited supra);Peyronie's syndrome; priapism; premature ejaculation; and any othercondition, disease or disorder, regardless of cause or origin, whichinterferes with at least one of the three phases of human sexualresponse, i.e., desire, excitement and orgasm (see Kaplan, Disorders ofSexual Desire (New York, N.Y. Brunner Mazel Book Inc., 1979)).

[0030] The terms “treating” and “treatment” as used herein refer toreduction in severity and/or frequency of symptoms, elimination ofsymptoms and/or underlying cause, prevention of the occurrence ofsymptoms and/or their underlying cause, and improvement or remediaton ofdamage. The present method of “treating” erectile dysfunction, as theterm is used herein, thus encompasses both prevention of the disorder ina predisposed individual and treatment of the disorder in a clinicallysymptomatic individual.

[0031] The term “phosphodiesterase inhibitor” as used herein is intendedto mean an agent that is capable of inhibiting or selectively reducingthe activity of any one or more phosphodiesterases.

[0032] The terms “active agent,” “drug” and “pharmacologically activeagent” are used interchangeably herein to refer to a chemical materialor compound that induces a desired effect. In the preferred embodimentherein, the terms refer to a phosphodiesterase inhibitor which iscapable of being delivered transmucosally. Included are derivatives andanalogs of those compounds or classes of compounds specificallymentioned which also induce the desired effect.

[0033] “Penetration enhancement” or “permeation enhancement” as usedherein relates to an increase in the permeability of the mucosal tissueto the selected pharmacologically active agent, i.e., so that the rateat which the drug permeates therethrough is increased.

[0034] “Carriers” or “vehicles” as used herein refer to carriermaterials suitable for transmucosal drug administration. Carriers andvehicles useful herein include any such materials known in the art whichis nontoxic and does not interact with other components of thecomposition in a deleterious manner.

[0035] By “transmucosal” drug delivery is meant administration of a drugto the mucosal surface of an individual so that the drug passes throughthe mucosal tissue and into the individual's blood stream. A preferredform of transmucosal drug delivery herein is “buccal” or “transbuccal”drug delivery which refer to delivery of a drug by passage of a drugthrough an individual's buccal mucosa and into the bloodstream. Anotherpreferred from of transmucosal drug delivery herein is “sublingual” or“transublingual” drug delivery which refer to delivery of a drug bypassage of a drug through an individual's sublingual mucosa and into thebloodstream. An additional preferred form of transmucosal drug deliveryherein is “rectal” or “transrectal” drug delivery which refer todelivery of a drug by passage of a drug through an individual's rectalmucosa and into the bloodstream.

[0036] By an “effective” amount of a drug or pharmacologically activeagent is meant a nontoxic but sufficient amount of the drug or agent toprovide the desired effect, i.e., treatment of erectile dysfunction.

[0037] Active Agents for Treatment of Erectile Dysfunction:

[0038] In order to carry out the method of the invention, a selectedphosphodiesterase inhibitor is administered transmucosally to anindividual prone to erectile dysfunction.

[0039] The active agent herein may be any agent which is effective toinhibit the activity of a phosphodiesterase. Suitable phosphodiesteraseinhibitors include, but are not limited to, inhibitors of the Type IIIphosphodiesterases (the cAMP-specific-cGMP inhibitable form), the TypeIV phosphodiesterase (the high affinity-high specificity cAMP form) andthe Type V phosphodiesterases (the cGMP specific form). Additionalinhibitors that may be used in conjunction with the present inventionare cGMP-specific phosphodiesterase inhibitors other than Type Vinhibitors.

[0040] Examples of Type III phosphodiesterase inhibitors that may beadministered herein include, but are not limited to, bipyridines such asmilrinone and amrinone; imidazolones such as piroximone and enoximone;imidazolines such as imazodan and 5-methyl-imazodan;dihydropyridazinones such as indolidan and LY181512

[0041] dihydroquinolinone compounds such as cilostamide, cilostazol,vesnarinone and OPC 3911

[0042] other compounds such as anagrelide, bemoradan, ibudilast,isomazole, lixazinone, motapizone, olprinone, phthalazinol, pimobendan,quazinone, siguazodan and trequinsin; and mixed Type III and Type IVinhibitors such as benafentrine,cis-6-[p-acetamidophenyl]-1,2,3,4,4a,10b-hexahydro-8,9-dimethoxy-2-methylbenzo-[c][1,6]-naphthyridine,EMD 54622(5-[1-(3,4-dimethoxybenzoyl)-4,4-dimethyl-1,2,3,4-tetrahydrochinolin-6-yl]-6-methyl-3,6-dihydro-1,3,4-thiadiazin-2-one),Org 20241 (N-hydroxy-4-[3,4-dimethoxyphenyl]-thiazole-2-carboximidamide), Org30029(N-hydroxy-5,6-dimethoxybenzo-[b]-thiophene-2-carboximidamide),saterinone, tolafentrine and zardaverine. Preferred Type III PDEinhibitors herein are bipyridines, imidazolones, imidazolines,dihydropyridazinones and dihydroquinolinone compounds. Of these, theinhibitors that are particularly preferred herein are milrinone,amrinone, piroximone, enoximone, imazodan, 5-methyl-imazodan, indolidan,cilostamide, cilostazol and vesnarinone. The inhibitors may be usedalone or in combination; if in combination, they may be administeredeither simultaneously or sequentially.

[0043] Examples of Type IV phosphodiesterase inhibitors that may beadministered herein include, but are not limited to: pyrrolidinones suchas rolipram (4-(3-cyclopentyloxy-4′-methoxyphenyl)-2-pyrrolidinone)) androlipram derivatives such as R020-1724(4-(3-butyloxy-4-methoxyphenyl)-imidazolidinone) and RS 33793(8-(3-nitrophenyl)-6-(3-methyl-2-butenyl)pyrido[2,3a]pyrazin-5-one);quinazolinediones such as nitraquazone (3-[3′-nitrophenyl]N-ethylquinazoline-2,6-dione), CP-77059(1-(carbomethoxyphenyl)-3-benzylpyrido[2,3d]pyrimidine-2,4(1H,3H)dione),RS-25344 (1-(3-nitrophenyl)-3-(4-pyridylmethyl)-1,2,3,4-tetrahydropyrido(2,3-d) pyrimidine-2,4-dione)) and other nitraquazone analogs;xanthine derivatives such as denbufylline(1,3-di-n-butyl-7-[2′-oxopropyl]xanthine), XT-44(1-n-butyl-3-n-propylxanthine), arofylline (LAS 31025;1-propyl-3-(4-chlorophenyl)-xanthine) and BRL 61063

[0044] phenyl ethyl pyridines such as CDP 840(4-(1-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl) pyridine) andcompounds disclosed in WO 97/22585 to Guay et al.; tetrahydropyrimidonessuch as atizoram (CP 80633)

[0045] diazepine derivatives such as C11018

[0046] and compounds disclosed in WO 97/36905 to Pascal et al.; oximecarbamates such as filaminast (PDA-641); naphthyridinones such as RS17597

[0047] benzofurans such as 2-butyl-7-methoxy-benzofuran-4-carboxylicacid (3,5-dichloro-pyridin-4-yl)-amide,2-benzyl-7-methoxy-benzofuran-4-carboxylic acid(3,5-dichloro-pyridin-4-yl)-amide,7-methoxy-2-phenethyl-benzofuran-4-carboxylic acid(3,5-dichloropyridin-4-yl)-amide and5-(2-butyl-7-methoxy-benzofuran-4-yl)-tetrahydro-pyrimidin-2-one,phenyldihydrobenzofurane compounds such as those disclosed in U.S. Pat.No. 5,902,824; 4-substituted benzofurane compounds such as thosedisclosed in EP 819688AI; substituted furans as disclosed in Perrier etal. Bioorg. Med. Chem. Lett. 9:323-326 (1999); naphthalene derivativessuch as T 440

[0048] purine derivatives such as V-12294A

[0049] imidazolidinones such as 1,3-dimethyl-2-imidazolidinone (DMI);cyclohexane carboxylic acids such as ariflo (SB 207499,(c-4-cyano-4-[3′-cyclopentyloxy-4′-methoxyphenyl]-r-1-cyclohexanecarboxylicacid)); benzamides such as piclamilast (RP73401;N-(3,5-dichloro-4-pyridyl)-3-cyclopentoxy-4-methoxy benzamide);benzothiophenes such as tibenelast (LY 186655); pyridopyridazinones suchas

[0050] substituted phenyl compounds, as disclosed in U.S. Pat. No.5,891,896 to Warrellow et al.; substituted biphenyl compounds asdisclosed in U.S. Pat. No. 5,877,190 to Dhainaut et al.; etazolate; andS-(+)-glaucine ((S)-(+)-1,2,9,10-tetramethoxyaporphine).

[0051] Examples of Type V phosphodiesterase inhibitors include, but arenot limited to, zaprinast, MY5445, dipyridamole, and sildenafil. OtherType V phosphodiesterase inhibitors are disclosed in PCT PublicationNos. WO 94/28902 and WO 96/16644.

[0052] The compounds described in PCT Publication No. WO 94/28902 arepyrazolopyrimidinones. Examples of the inhibitor compounds include5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-(5-morphol inoacetyl-2-n-propoxyphenyl)1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-allyloxy-5-(4-methyl-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-ethoxy-5-[4-(2-propyl)-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[5-[4-(2-hydroxyethyl)-1-piperazinylsulfonyl]-2-n-propoxyphenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,and5-[2-ethoxy-5-(1-methyl-2-imidazolyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

[0053] The phosphodiesterase inhibitors described in PCT Publication No.WO 96/16644 include griseolic acid derivatives, 2-phenylpurinonederivatives, phenylpyridone derivatives, fused and condensedpyrimidines, pyrimidopyrimidine derivatives, purine compounds,quinazoline compounds, phenylpyrimidinone derivative,imidazoquinoxalinone derivatives or aza analogues thereof,phenylpyridone derivatives, and others. Specific examples of thephosphodiesterase inhibitors disclosed in WO 96/16644 include1,3-dimethyl-5-benzylpyrazolo[4,3-d]pyrimidine-7-one,2-(2-propoxyphenyl)-6-purinone,6-(2-propoxyphenyl)-1,2-dihydro-2-oxypyridine-3-carboxamide,2-(2-propoxyphenyl)-pyrido[2,3-d]pyrimid-4(3H)-one,7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydro-pyrimido[4,5-d]pyrimidine,6-hydroxy-2-(2-propoxyphenyl)pyrimidine-4-carboxamide,1-ethyl-3-methylimidazo[1,5a]quinoxalin-4(5H)-one,4-phenylmethylamino-6-chloro-2-(1-imidazoloyl)quinazoline,5-ethyl-8-[3-(N-cyclohexyl-N-methylcarbamoyl)-propyloxy]-4,5-dhydro-4-oxo-pyrido[3,2-e]-pyrrolo[1,2-a]pyrazine,5′-methyl-3′-(phenylmethyl)-spiro[cyclopentane-1,7′(8′H)-(3′H)-imidazo[2,1-b]purin]4′(5′H)-one,1-[6-chloro-4-(3,4-methylenedioxybenzyl)-aminoquinazolin-2-yl)piperidine-4-carboxylicacid, (6R,9S)-2-(4-trifluoromethyl-phenyl)methyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]-imidazo[2,1-b]-purin-4-one,1-t-butyl-3-phenylmethyl-6-(4-pyridyl)pyrazolo[3,4-d]-pyrimid-4-one,1-cyclopentyl-3-methyl-6-(4-pyridyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimid-4-one,2-butyl-1-(2-chlorobenzyl)6-ethoxy-carbonylbenzimidazole, and2-(4-carboxypiperidino)-4-(3,4-methylenedioxy-benzyl)amino-6-nitroquinazoline,and 2-phenyl-8-ethoxycycloheptimidazole.

[0054] Still other Type V phosphodiesterase inhibitors useful inconjunction with the present invention include: IC-351 (ICOS);4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)propoxy]-3(2H)pyridazinone;1-[4-[(1,3-benzodioxol-5-ylmethyl)amiono]-6-chloro-2-quinazolinyl]-4-piperidine-carboxylicacid, monosodium salt;(+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-methyl-cyclopent-4,5]imidazo[2,1-b]purin-4(3H)one;furazlocillin;cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]imidazo[2,1-b]purin-4-one;3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate;4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl)propoxy)-3-(2H)pyridazinone;1-methyl-5-(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one;1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyll-4-piperidinecarboxylicacid, monosodium salt; pyrrolo[1,2-c]imidazolone derivatives (asdescribed in U.S. Pat. No. 4,937,258 to Shaw);1-phenylmethyl-N-[[4-ethyl-2-(2-ethyl-4-methyl-1H-imidazol-1-yl)]pyrimidin-5-yl]-1H-imidazol-2-carboxamide;1-phenylmethyl-N-[4-ethyl-2-(1H-imidazol-1-yl)pyrimidin-5-yl]-1H-imidazol-2-carboxamide(see U.S. Pat. No. 5,318,975 to Lis);4,9-diethyl-2-(2-ethyl-4-methyl-1H-imidazol-1-yl)-7-methylimidazo[5,1-h]pteridin-6(5H)-one;and9-ethyl-2(2-ethyl-4-methyl-1H-imidazol-1-yl)-7-methyl-4-(2-propyl)imidazo[5,1-h]pteridin-6(5H)-one(see U.S. Pat. No. 5,602,252 to Davey); Pharmaprojects No. 4516 (GlaxoWellcome); Pharmaprojects No. 5051 (Bayer); Pharmaprojects No. 5064(Kyowa Hakko; see WO 96/26940); Pharmaprojects No. 5069 (ScheringPlough); GF-196960 (Glaxo Wellcome); and Sch-51866.

[0055] Other phosphodiesterase inhibitors that may be co-administeredwith the Type III PDE inhibitor include nonspecific phosphodiesteraseinhibitors such as aminophylline, enprofylline, isbufylline, IBMX,papaverine, pentoxifylline, theobromine and theophylline, and directvasodilators such as hydralazine.

[0056] The active agents may be administered, if desired, in the form ofsalts, esters, amides, prodrugs, derivatives, and the like, provided thesalt, ester, amide, prodrug or derivative is suitable pharmacologically,i.e., effective in the present method. Salts, esters, amides, prodrugsand other derivatives of the active agents may be prepared usingstandard procedures known to those skilled in the art of syntheticorganic chemistry and described, for example, by J. March, AdvancedOrganic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (NewYork: Wiley-Interscience, 1992). For example, acid addition salts areprepared from the free base using conventional methodology, and involvesreaction with a suitable acid. Generally, the base form of the drug isdissolved in a polar organic solvent such as methanol or ethanol and theacid is added thereto. The resulting salt either precipitates or may bebrought out of solution by addition of a less polar solvent. Suitableacids for preparing acid addition salts include both organic acids,e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalicacid, malic acid, malonic acid, succinic acid, maleic acid, fumaricacid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like, as well as inorganic acids, e.g.,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. An acid addition salt may be reconvertedto the free base by treatment with a suitable base. Particularlypreferred acid addition salts of the active agents herein are halidesalts, such as may be prepared using hydrochloric or hydrobromic acids.Conversely, preparation of basic salts of acid moieties which may bepresent on a phosphodiesterase inhibitor molecule are prepared in asimilar manner using a pharmaceutically acceptable base such as sodiumhydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide,trimethylamine, or the like. Particularly preferred basic salts hereinare alkali metal salts, e.g., the sodium salt, and copper salts.Preparation of esters involves functionalization of hydroxyl and/orcarboxyl groups which may be present within the molecular structure ofthe drug. The esters are typically acyl-substituted derivatives of freealcohol groups, i.e., moieties which are derived from carboxylic acidsof the formula RCOOH where R is alkyl, and preferably is lower alkyl.Esters can be reconverted to the free acids, if desired, by usingconventional hydrogenolysis or hydrolysis procedures. Amides andprodrugs may also be prepared using techniques known to those skilled inthe art or described in the pertinent literature. For example, amidesmay be prepared from esters, using suitable amine reactants, or they maybe prepared from an anhydride or an acid chloride by reaction withammonia or a lower alkyl amine. Prodrugs are typically prepared bycovalent attachment of a moiety which results in a compound that istherapeutically inactive until modified by an individual's metabolicsystem.

[0057] Pharmaceutical Formulations and Modes of Administration:

[0058] The active agent is administered transmucosally to treat erectiledysfunction, and is accordingly administered in a pharmaceuticalformulation suitable for transmucosal drug administration.

[0059] The pharmaceutical compositions may be in the form of solid,semi-solid or liquid dosage forms, such as, for example, buccal tablets,sublingual tablets, rectal suppositories, suspensions, creams,ointments, solutions, lotions, pastes or the like, preferably in unitdosage form suitable for single administration of a precise dosage. Thecompositions comprise an effective amount of the phosphodiesteraseinhibitor in combination with a pharmaceutically acceptable carrier and,in addition, may include other pharmaceutical agents, adjuvants,diluents, buffers, etc.

[0060] For solid compositions, conventional nontoxic solid carriersinclude, for example, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose,sucrose, magnesium carbonate, and the like. Liquid pharmaceuticallyadministrable compositions can, for example, be prepared by dissolving,dispersing, etc., an active compound as described herein and optionalpharmaceutical adjuvants in an excipient, such as, for example, water,saline, aqueous dextrose, glycerol, ethanol, and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like, for example, sodium acetate, sorbitanmonolaurate, triethanolamine sodium acetate, triethanolamine oleate,etc. Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington: TheScience and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: MackPublishing Company, 1995).

[0061] Depending on the particular phosphodiesterase inhibitoradministered, it may be desirable to incorporate a permeation enhancerin the formulation in order to increase the rate at which the activeagent permeates through the mucosal tissue to which it is applied, e.g.,the buccal mucosa, sublingual or rectal mucosa. Examples of suitablepermeation enhancers include dimethylsulfoxide (“DMSO”), dimethylformamide (“DMF”), N,N-dimethylacetamide (“DMA”), decylmethylsulfoxide(“DMSO”), polyethylene glycol monolaurate (“PEGML”), glycerolmonolaurate, lecithin, the 1-substituted azacycloheptan-2-ones,particularly 1-n-dodecylcyclazacycloheptan-2-one (available under thetrademark Azone® from Nelson Research & Development Co., Irvine,Calif.), SEPA® (available from Macrochem Co., Lexington, Mass.),alcohols (e.g., ethanol), surfactants as discussed above, including, forexample, Tergitol®, Nonoxynol-9® and TWEEN-80®, and lower alkanols suchas ethanol.

[0062] The formulations may additionally include one or more enzymeinhibitors effective to inhibit drug-degrading enzymes which may bepresent at the site of administration. Such enzyme inhibiting compoundsmay be determined by those skilled in the art by reference to thepertinent literature and/or using routine experimental methods.Additional optional components include excipients, binders, fillers,lubricants (e.g., stearates such as magnesium stearate), preservatives(e.g., antioxidants), chelating agents, solubilizing agents (e.g.,surfactants), and the like, as will be appreciated by those skilled inthe art of drug formulation preparation and delivery.

[0063] Transmucosal drug may involve administration of any type offormulation or dosage unit suitable for application to the mucosaltissue. For example, the selected active agent may be administered in anointment, cream, paste, or the like, or in a solid dosage form unit tobe placed under the tongue (sublingual formulations), affixed to thebuccal mucosa as an adhesive tablet or patch (buccal formulations), orplaced within or near the rectum (transrectal formulations).

[0064] Preferred buccal dosage forms will typically comprise atherapeutically effective amount of the selected phosphodiesteraseinhibitor and a bioerodible (hydrolyzable) polymeric carrier that mayalso serve to adhere the dosage form to the buccal mucosa. The buccaldosage unit is fabricated so as to erode gradually over a predeterminedtime period, wherein drug delivery is provided essentially throughout.The time period is typically in the range of approximately 0.5 hours to24 hours. Buccal drug delivery, as will be appreciated by those skilledin the art, avoids the disadvantages encountered with oral drugadministration, e.g., slow absorption, degradation of the active agentby fluids present in the gastrointestinal tract and/or first-passinactivation in the liver. The “therapeutically effective amount” ofphosphodiesterase inhibitor in the dosage unit will of course depend onthe potency of the agent and the intended dosage, which, in turn, isdependent on the particular individual undergoing treatment, thespecific indication, and the like. Suitable doses of specificphosphodiesterase inhibitors will be known to those skilled in the art,or may be deduced from the literature in combination with the teachingof the present disclosure. By way of example, a typical daily dosage ofsildenafil citrate for treatment of sexual dysfunction as discussedherein is in the range of about 25 to 100 mg, although more or less maybe effective. The dosage unit will generally contain from approximately1.0 wt. % to about 60 wt. % active agent, preferably on the order of 1wt. % to about 30 wt. % active agent. With regard to the bioerodible(hydrolyzable) polymeric carrier, it will be appreciated that virtuallyany such carrier can be used, so long as the desired drug releaseprofile is not comprised, and the carrier is compatible with thephosphodiesterase inhibitor to be administered and any other componentsthat may be present in the buccal dosage unit. Generally, the polymericcarrier comprises hydrophilic (water-soluble and water-swellable)polymers that adhere to the wet surface of the buccal mucosa. Examplesof polymeric carriers useful herein include acrylic acid polymers andco, e.g., those known as “carbomers” (Carbopol®, which may be obtainedfrom B. F. Goodrich, is one such polymer). Other suitable polymersinclude, but are not limited to: hydrolyzed polyvinylalcohol;polyethylene oxides (e.g., Sentry Polyox® water soluble resins,available from Union Carbide); polyacrylates (e.g., Gantrez®, which maybe obtained from GAF); vinyl polymers and copolymers;polyvinylpyrrolidone; dextran; guar gum; pectins; starches; andcellulosic polymers such as hydroxypropyl methylcellulose, (e.g.,Methocel®, which may be obtained from the Dow Chemical Company),hydroxypropyl cellulose (e.g., Klucel®, which may also be obtained fromDow), hydroxypropyl cellulose ethers (see, e.g., U.S. Pat. No. 4,704,285to Alderman), hydroxyethyl cellulose, carboxymethyl cellulose, sodiumcarboxymethyl cellulose, methyl cellulose, ethyl cellulose, celluloseacetate phthalate, cellulose acetate butyrate, and the like.

[0065] Other components may also be incorporated into the buccal dosageforms described herein. The additional components include, but are notlimited to, disintegrants, diluents, binders, lubricants, flavoring,colorants, preservatives, and the like. Examples of disintegrants thatmay be used include, but are not limited to, cross-linkedpolyvinylpyrrolidones, such as crospovidone (e.g., Polyplasdone® XL,which may be obtained from GAF), cross-linked carboxylicmethylcelluloses, such as croscarmelose (e.g., Ac-di-sol®, which may beobtained from FMC), alginic acid, and sodium carboxymethyl starches(e.g., Explotab®, which may be obtained from Edward Medell Co., Inc.),methylcellulose, agar bentonite and alginic acid. Suitable diluents arethose which are generally useful in pharmaceutical formulations preparedusing compression techniques, e.g., dicalcium phosphate dihydrate (e.g.,Di-Tab®, which may be obtained from Stauffer), sugars that have beenprocessed by cocrystallization with dextrin (e.g., co-crystallizedsucrose and dextrin such as Di-Pakg, which may be obtained from Amstar),lactone, calcium phosphate, cellulose, kaolin, mannitol, sodiumchloride, dry starch, powdered sugar and the like. Binders, if used, arethose that enhance adhesion. Examples of such binders include, but arenot limited to, starch, gelatin and sugars such as sucrose, dextrose,molasses, and lactose. Particularly preferred lubricants are stearatesand stearic acid, and an optimal lubricant is magnesium stearate.

[0066] Preferred sublingual dosage forms include sublingual tablets,creams, ointments and pastes. The tablet, cream, ointment or paste forsublingual delivery comprises a therapeutically effective amount of theselected phosphodiesterase inhibitor and one or more conventionalnontoxic carriers suitable for sublingual drug administration. Thesublingual dosage forms of the present invention can be manufacturedusing conventional processes. The sublingual dosage unit is fabricatedto disintegrate rapidly. The time period for complete disintegration ofthe dosage unit is typically in the range of from about 10 seconds toabout 30 minutes, and optimally is less than 5 minutes.

[0067] Other components may also be incorporated into the sublingualdosage forms described herein. The additional components include, butare not limited to binders, disintegrators, wetting agents, lubricants,and the like. Examples of binders that may be used include water,ethanol, polyvinylpyrrolidone, starch solution gelatin solution, and thelike. Suitable disintegrators include dry starch, calcium carbonate,polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate,stearic monoglyceride, lactose, and the like. Wetting agents, if used,include glycerin, starches, and the like. Particularly preferredlubricants are stearates and polyethylene glycol. Additional componentsthat may be incorporated into sublingual dosage forms are known, or willbe apparent, to those skilled in this art; for example, see Remington:The Science and Practice of Pharmacy, 19th edition (Mack Publishing,1995).

[0068] Preferred transrectal dosage forms include rectal suppositories,creams, ointments, and liquid formulations (enemas). The suppository,cream, ointment or liquid formulation for transrectal delivery comprisesa therapeutically effective amount of the selected phosphodiesteraseinhibitor and one or more conventional nontoxic carriers suitable fortransrectal drug administration. The transrectal dosage forms of thepresent invention can be manufactured using conventional processes. Thetransrectal dosage unit can be fabricated to disintegrate rapidly orover the period of several hours. The time period for completedisintegration is preferably in the range of from about 10 minutes toabout 6 hours, and optimally is less than 3 hours.

[0069] Other components may also be incorporated into the transrectaldosage forms described herein. The additional components include, butare not limited to, stiffening agents, antioxidants, preservatives, andthe like. Examples of stiffening agents that may be used include, forexample, paraffin, white wax and yellow wax. Preferred antioxidants, ifused, include sodium bisulfite and sodium metabisulfite.

[0070] Ointments, as is well known in the art of pharmaceuticalformulation, are semisolid preparations that are typically based onpetrolatum or other petroleum derivatives. Creams containing theselected active agent, are, as known in the art, viscous liquid orsemisolid emulsions, either oil-in-water or water-in-oil. Cream basesare water-washable, and contain an oil phase, an emulsifier and anaqueous phase. The oil phase, also called the “internal” phase, isgenerally comprised of petrolatum and a fatty alcohol such as cetyl orstearyl alcohol. The aqueous phase usually, although not necessarily,exceeds the oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation is generally a nonionic, anionic,cationic or amphoteric surfactant. The specific ointment or cream baseto be used, as will be appreciated by those skilled in the art, is onethat will provide for optimum drug delivery. As with other carriers orvehicles, an ointment base should be inert, stable, nonirritating andnonsensitizing. The ointment or cream is applied to a suitable mucosalsurface.

[0071] Pastes are semisolid dosage forms in which the active agent issuspended in a suitable base. Depending on the nature of the base,pastes are divided between fatty pastes or those made from asingle-phase aqueous gels. The base in a fatty paste is generallypetrolatum or hydrophilic petrolatum or the like. The pastes made fromsingle-phase aqueous gels generally incorporate carboxymethylcelluloseor the like as a base. The paste is applied to a suitable mucosalsurface.

[0072] Suppositories are solid dosage forms in which the active agent iscarried in a suitable base. Specifically shaped for insertion into bodyorifices, the suppository melts, softens or dissolves resulting ineffective delivery of the active agent. The suppository base can be anoleaginous base, water-soluble base, or mixture of both. The base mustremain a solid at room temperature but melt, soften or dissolve at bodytemperature. Thus, suitable suppository bases include, for example,cocoa butter, glyceryl monostearate and polyethylene glycol. Thesuppository is made using conventional techniques including molding,compression, or hand rolling. The suppository is inserted into a bodyorifice having a suitable mucosal surface.

[0073] Enemas are liquid dosage forms in which the active agent issolubilized or suspended in a suitable liquid carrier. As will bereadily apparent to those skilled in the art, the selection of theliquid carrier is dependent upon the stability and chemical reactivityof the active agent. Suitable liquid carriers for enemas include, forexample, sodium chloride solution. Alternative carriers, additionalcomponents and methods of preparing enemas are known to those skilled inthe art or disclosed in Remington: The Science and Practice of Pharmacy,referenced above.

[0074] Additional pharmacologically active agents may be delivered alongwith the primary active agent, i.e., the phosphodiesterase inhibitor.Vasoactive agents, particularly vasodilators, are preferred additionalagents. Suitable vasoactive agents include, but are not limited to,nitrovasodilators such as: nitroglycerin; linsidomine, particularlylinsidomine chlorhydrate (“SIN-I”); molsidomine; organic nitrates suchas isosorbide dinitrate, erythrityl tetranitrate and amyl nitrate;sodium nitroprusside; S-nitrosothiols such asS-nitroso-N-acetyl-d,l-penicillamine (“SNAP”), S-nitroso-N-cysteine andS-nitroso-N-glutathione (“SNO-GLU”); and diazenium diolates (“NONOates”)such as(Z)-1-{N-methyl-N-[6-(N-methyl-ammoniohexyl)amino]}diazen-1-ium-1,2-diolate,(Z)-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate,(Z)-1-{N-[3-aminopropyl]-N-[4-(3-aminopropylammonio)butyl]amino}diazen-1-ium-1,2-diolateand sodium (Z)-1-(N,N-diethylamino)-diazen-1-ium-1,2-diolate. Othersuitable vasoactive agents include, for example, long and shortacting-blockers such as phenoxybenzamine, dibenamine, doxazosin,terazosin, phentolamine, tolazoline, prazosin, trimazosin, alfuzosin,tamsulosin and indoramin; ergot alkaloids such as ergotamine andergotamine analogs, e.g., acetergamine, brazergoline, bromerguride,cianergoline, delorgotrile, disulergine, ergonovine maleate, ergotaminetartrate, etisulergine, lergotrile, lysergide, mesulergine, metergoline,metergotamine, nicergoline, pergolide, propisergide, proterguride andterguride; antihypertensive agents such as diazoxide, hydralazine andminoxidil; vasodilators such as nimodipine, pinacidil, cyclandelate andisoxsuprine; chlorpromazine; haloperidol; yohimbine; Rec 15/2739;trazodone; naturally occurring prostaglandins such as PGE₀, PGE₁, PGA₂,PGB₁, PGF₁, 19-hydroxy-PGA₁, 19-hydroxy-PGB₁, PGE₂, PGA₂, PGB₂,19-hydroxy-PGA₂, 19-hydroxy-PGB₂, PGE₃, PGF₃; semisynthetic or syntheticderivatives of natural prostaglandins, including carboprosttromethamine, dinoprost tromethamine, dinoprostone, lipoprost,gemeprost, metenoprost, sulprostone and tiaprost; and vasoactiveintestinal peptide. Prazosin, prostaglandin E₀, prostaglandin E₁ andprostaglandin E₂ are particularly preferred vasoactive agents to beco-administered with the active agent.

[0075] The amount of active agent administered and the dosing regimenused, will, of course, be dependent on the particular drug selected, theage and general condition of the subject being treated, the severity ofthe subject's condition, and the judgment of the prescribing physician.A typical daily dose of an active agent as administered transmucosally,e.g., buccally, sublingually, or transrectally, is generally in therange of approximately 0.1 to 500 mg, with 5 mg to 100 mg representingan optional dosage range for most active agents. Depending on thehalf-life of the drug and the availability via the chosen route ofadministration, the dosing regimen can be modulated in order to achievesatisfactory therapeutic results.

[0076] Kits:

[0077] The invention also encompasses a kit for patients to carry outthe present method of treating premature ejaculation using transmucosal,e.g., buccal, sublingual, and transrectal drug therapy. The kit containsthe pharmaceutical formulation to be administered, a container,preferably sealed, for housing the formulation during storage and priorto use, and instructions for carrying out drug administration in aneffective manner. The formulation may consist of the drug in unit dosageform. The kit may contain multiple formulations of different dosages ofthe same agent. The kit may also contain multiple formulations ofdifferent active agents. The instructions may be in written orpictograph form, or can be on recorded media including audio tape, videotape, or the like.

[0078] Use in Conjunction With Venous Flow Control (“VFC”) Device:

[0079] In an alternative embodiment of the invention, a pharmaceuticalformulation containing the selected phosphodiesterase inhibitor isadministered transmucosally in combination with use of a venous flowcontrol device such as that described in U.S. Pat. No. 5,855,548 toPlace for “Venous Flow Control Element for Maintaining Penile Erection,”assigned to VIVUS, Inc. (Mountain View, Calif.). Preferred devices areformed from a length of flexible tubing having an integral fasteningmeans, so as to provide for readily adjustable venous flow control whenapplied to the penis. The device is applied to the base of the penisprior to and during sexual intercourse, such that it effectivelyenhances retention of blood within the penis without substantiallyobstructing arterial inflow or becoming too constrictive during theerectile process. In this embodiment, a kit will include the venous flowcontrol device in addition to the components noted above, along withinstructions for using the device.

[0080] It is to be understood that while the invention has beendescribed in conjunction with the preferred specific embodimentsthereof, that the foregoing description as well as the examples whichfollow are intended to illustrate and not limit the scope of theinvention. Other aspects, advantages and modifications within the scopeof the invention will be apparent to those skilled in the art to whichthe invention pertains. All patents, patent applications, andpublications mentioned herein are hereby incorporated by reference intheir entireties.

EXAMPLE 1

[0081] Preparation of transmucosal paste: A transinucosal formulation isprepared containing zaprinast, a Type V phosphodiesterase inhibitor. 10g of bulk zaprinast is placed in a mortar and a pestle is used to grindthe solid into a fine powder. About 10 g of a previously weighed outquantity of 100 g of OPABASE® (Colgate-Hoyt Laboratories, Norwood,Mass.) is combined with the zaprinast powder on an ointment tile. Thezaprinast powder and ORABASE® are levigated together using a spatula.The remaining ORABASE® is added to the ointment tile and levigated withthe previously mixed components to produce a smooth, consistentformulation. The resulting formulation is a 10% zaprinast transmucosalformulation.

[0082] This procedure can be used with various phosphodiesteraseinhibitors, ointment bases and additional components, e.g., enhancers orthe like.

EXAMPLE 2

[0083] Preparation of transmucosal paste: A transmucosal formulation isprepared containing sildenafil citrate, a Type V phosphodiesteraseinhibitor. About 5 g of bulk sildenafil citrate is placed in a mortarand a pestle is used to grind the solid into a fine powder. About 5 g ofa previously weighed out quantity of 100 g of ORABASE® is combined withthe sildenafil citrate powder on an ointment tile. The sildenafilcitrate powder and ORABASE® are levigated together using a spatula. Theremaining ORABASE® is added to the ointment tile and levigated with thepreviously mixed components to produce a smooth, consistent formulation.The resulting formulation is a 5% sildenafil citrate transmucosalformulation.

EXAMPLE 3

[0084] Preparation of buccal dosage form: 10 g of zaprinast and 90 g ofgelatin are mixed and pulverized in a mill. After the mixing iscomplete, 20 g of concentrated glycerin, 10 g of lactose and 20 g ofmannitol are added and the components are mixed until uniform. 150 mgaliquot portions of the mixture are compression-molded to provide abuccal dosage unit. Each buccal unit contains 10 mg of zaprinast.

EXAMPLE 4

[0085] Preparation of a buccal dosage form: 10 g of sildenafil citrateand 90 g of gelatin are mixed and pulverized in a mill. After the mixingis complete, 20 g of concentrated glycerin, 10 g of lactose and 20 g ofmannitol are added and the components are mixed until uniform. 150 mgaliquot portions of the mixture are compression-molded to provide abuccal dosage unit. Each buccal unit contains 10 mg of sildenafilcitrate.

EXAMPLE 5

[0086] Preparation of a buccal dosage form: 10 g of milrinone (a TypeIII phosphodiesterase inhibitor) and 90 g of gelatin are mixed andpulverized in a mill. After the mixing is complete, 20 g of concentratedglycerin, 10 g of lactose and 20 g of mannitol are added and thecomponents are mixed until uniform. 150 mg aliquot portions of themixture are compression-molded to provide a buccal dosage unit. Eachbuccal unit contains 10 mg of milrinone.

EXAMPLE 6

[0087] Preparation of a buccal dosage form: 10 g of rolipram (a Type IVphosphodiesterase inhibitor) and 90 g of gelatin are mixed andpulverized in a mill. After the mixing is complete, 20 g of concentratedglycerin, 10 g of lactose and 20 g of mannitol are added and thecomponents are mixed until uniform. 150 mg aliquot portions of themixture are compression-molded to provide a buccal dosage unit. Eachbuccal unit contains 10 mg of rolipram.

EXAMPLE 7

[0088] 10074] Preparation of a sublingual tablet: 1.0 g of zaprinast,1.0 g of mannitol, 2.0 g of microcrystalline cellulose, and 10 mg ofmagnesium stearate are blended in a suitable mixer and then compressedinto sublingual tablets. Each sublingual tablet contains 10 mg ofzaprinast.

EXAMPLE 8

[0089] Preparation of a sublingual tablet: 1.0 g of sildenafil citrate,1.0 g of mannitol, 2.0 g of microcrystalline cellulose, and 10 mg ofmagnesium stearate are blended in a suitable mixer and then compressedinto sublingual tablets. Each sublingual tablet contains 10 mg ofsildenafil citrate.

EXAMPLE 9

[0090] Preparation of a rectal suppository: A pharmaceutical formulationcontaining a Type V phosphodiesterase inhibitor for transrectaladministration is prepared by mixing 10 to 100 mg zaprinast withpolyethylene glycol, molecular weight approximately 4000, and heatingthe mixture to a temperature just high enough to produce azaprinast-polymer melt. The zaprinast-polyethyleneglycol mixture canthen be poured into a mold suitable to provide a zaprinast rectalsuppository, and allowed to cool. The suppository so provided is a unitdosage form suitable for transrectal administration.

EXAMPLE 10

[0091] Preparation of a rectal suppository: A phannaceutical formulationcontaining an a Type V phosphodiesterase inhibitor for transrectaladministration is prepared by mixing to 100 mg sildenafil citrate withpolyethylene glycol, molecular weight approximately 4000, and heatingthe mixture to a temperature just high enough to produce a sildenafilcitrate-polymer melt. The sildenafil citrate-polyethyleneglycol mixturecan then be poured into a mold suitable to provide a sildenafil citraterectal suppository, and allowed to cool. The suppository so provided isa unit dosage form suitable for transrectal administration.

EXAMPLE 11

[0092] An effective phosphodiesterase-inhibiting dose may be determinedusing the following procedures.

[0093] Buccal administration: Patients with penile vascularinsufficiency are given a single dose of 0.5 g of a phosphodiesteraseinhibitor (e.g., zaprinast) transbucally in a buccal dosage form. Priorto and approximately 3 hours after administering the inhibitor, bloodsamples are taken and assayed for plasma phosphodiesterase activityusing, for example, high-performance liquid chromatography withfluorimetric detection as described by Lee et al, J. Chromatography421:237-244 (1987). This procedure is repeated at 24 hour intervals withdosage adjusted as necessary.

[0094] Sublingual administration: The same procedures described fordetermining an effective phosphodiesterase-inhibiting dose for buccaladministration are followed except that a suitable dosage form isadministered sublingually.

[0095] Transrectal administration: The same procedures described fordetermining an effective phosphodiesterase-inhibiting dose for buccaladministration are followed expect that a suitable dosage form isadministered transrectally.

EXAMPLE 12

[0096] The pharmaceutical formulations of Examples 1-10 can be used totreat erectile dysfunction in individuals in which the dysfunction isassociated, for example, vascular insufficiency. Dosage may be adjustedusing the methodology of Example 11. In all instances, the individualsare expected to respond positively, although variations in the intensityand duration of erection may be observed depending on dose, formulation,and environment. Generally, between approximately 5 and 90 minutesfollowing drug administration, it is expected that an erection may beachieved.

What is claimed is:
 1. A pharmaceutical formulation for treatingerectile dysfunction in an individual and suitable for transmucosal drugadministration, comprising a therapeutically effective amount of aphosphodiesterase inhibitor, a carrier suitable for transmucosal drugadministration, and, optionally, a permeation enhancer.
 2. Theformulation of claim 1, wherein the formulation comprises a solid dosageform for application to buccal mucosa, and the carrier is suitable fortransbuccal drug delivery.
 3. The formulation of claim 2, wherein thecarrier is a hydrolyzable polymer.
 4. The formulation of claim 3,wherein the dosage form further comprises an adhesive suitable foraffixing the dosage form to the buccal mucosa.
 5. The formulation ofclaim 2, wherein the phosphodiesterase inhibitor representsapproximately 1 wt % to 30 wt % of the buccal solid dosage form.
 6. Theformulation of claim 2, wherein the buccal solid dosage form contains atleast one additional component selected from the group consisting ofdisintegrants, diluents, binders, lubricants, flavoring, colorants, andpreservatives.
 7. The formulation of claim 1, wherein the formulationcomprises a dosage form for application to sublingual mucosa, and thecarrier is suitable for sublingual drug delivery.
 8. The formulation ofclaim 7, wherein the sublingual dosage form completely disintegrates inless than five minutes after administration.
 9. The formulation of claim7, wherein the sublingual dosage form contains at least one additionalcomponent selected from the group consisting of binders, disintegrators,wetting agents, and lubricants.
 10. The formulation of claim 1, whereinthe formulation comprises a dosage form for application to rectalmucosa, and the carrier is suitable for transrectal drug delivery. 11.The formulation of claim 10, wherein the transrectal dosage formcompletely disintegrates within approximately 3 hours followingadministration.
 12. The formulation of claims 11, wherein thetransrectal dosage form is a rectal suppository.
 13. The formulation ofclaim 12, wherein the rectal suppository further includes at least oneadditional component selected from the group consisting of stiffeningagents, antioxidants, and preservatives.
 14. The formulation of claim 1,wherein the phosphodiesterase inhibitor is a Type III phosphodiesteraseinhibitor.
 15. The formulation of claim 14, wherein the Type IIIphosphodiesterase inhibitor is selected from the group consisting ofbipyridines, imidazolones, imidazolines, dihydropyridazinones,dihydroquinolones, mixed Type III-Type IV inhibitors, anagrelide,bemoradan, ibudilast, isomazole, lixazinone, motapizone, olprinone,phthalazinol, pimobendan, quazinone, siguazodan and trequinsin.
 16. Theformulation of claim 15, wherein the Type III phosphodiesteraseinhibitor is a bipyridine.
 17. The formulation of claim 16, wherein thebipyridine is selected from the group consisting of amrinone andmilrinone.
 18. The formulation of claim 15, wherein the Type IIIphosphodiesterase inhibitor is an imidazolone.
 19. The formulation ofclaim 18, wherein the imidazolone is selected from the group consistingof piroximone and enoximone.
 20. The formulation of claim 15, whereinthe Type III phosphodiesterase inhibitor is a dihydroquinolinone. 21.The formulation of claim 20, wherein the dihydroquinolinone is selectedfrom the group consisting of cilostamide, cilostazol, vesnarinone andOPC
 3911. 22. The formulation of claim 1, wherein the phosphodiesteraseinhibitor is a Type IV phosphodiesterase inhibitor.
 23. The formulationof claim 22, wherein the Type IV phosphodiesterase inhibitor is selectedfrom the group consisting of pyrrolidinones, quinazolinediones, xanthinederivatives, phenyl ethyl pyridines, tetrahydropyrimidones, diazepinederivatives, oxime carbamates, naphthyridinones, benzofurans,naphthalene derivatives, purine derivatives, imidazolidinones,cyclohexane carboxylic acids, benzamides, benzothiophenes,pyridopyridazinones, etazolate, S-(+)-glaucine, substituted phenylcompounds, and substituted biphenyl compounds.
 24. The formulation ofclaim 23, wherein the Type IV phosphodiesterase inhibitor is apyrrolidinone.
 25. The formulation of claim 24, wherein thepyrrolidinone is selected from the group consisting of rolipram,R020-1724 and RS
 33793. 26. The formulation of claim 25, wherein thepyrrolidinone is rolipram.
 27. The formulation of claim 1, wherein thephosphodiesterase inhibitor is a Type V phosphodiesterase inhibitor. 28.The formulation of claim 27, wherein the Type V phosphodiesteraseinhibitor is selected from the group consisting of zaprinast; MY 544;dipyridamole; sildenafil; pyrazolopyrimidinones; griseolic acidderivatives; 2-phenylpurinones; phenylpyridone derivatives; pyrimidines;pyrimidopyrimidines; purines; quinazolines; phenylpyrimidinones;imidazoquinoxalinones or aza analogues thereof; phenylpyridones; 1C-351(ICOS); 4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)propoxy]-3(2H)pyridazinone;1-[4-[(1,3-benzodioxol-5-ylmethyl)amiono]-6-chloro-2-quinazolinyl]-4-piperidine-carboxylicacid, monosodium salt;(+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-methyl-cyclopent-4,5]imidazo[2,1-b]purin-4(3H)one;furazlocillin;cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]imidazo[2,1-b]purin-4-one;3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate;4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl)propoxy)-3-(2H)pyridazinone;1-methyl-5-(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one;1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyl]-4-piperidinecarboxylicacid, monosodium salt; pyrrolo[1,2-c]imidazolone derivatives;1-phenylmethyl-N-[[4-ethyl-2-(2-ethyl-4-methyl-1H-imidazol-1-yl)]pyrimidin-5-yl]-1H-imidazol-2-carboxamide;1-phenylmethyl-N-[4-ethyl-2-(1H-imidazol-1-yl)pyrimidin-5-yl-]H-imidazol-2-carboxamide;4,9-diethyl-2-(2-ethyl-4-methyl-1H-imidazol-1-yl)-7-methylimidazo[5,1-h]pteridin-6(5H)-one;and9-ethyl-2(2-ethyl-4-methyl-1H-imidazol-1-yl)-7-methyl-4-(2-propyl)imidazo[5,1-h]pteridin-6(5H)-one.29. The formulation of claim 28, wherein the Type V phosphodiesteraseinhibitor is zaprinast.
 30. The formulation of claim 28, wherein theType V phosphodiesterase inhibitor is a pyrazolopyrimidinone.
 31. Theformulation of claim 28, wherein the Type V phosphodiesterase inhibitoris sildenafil or a pharmaceutically acceptable salt thereof.
 32. Theformulation of claim 1, wherein the phosphodiesterase inhibitor isselected from the group consisting of pentoxifylline, papaverine,doxazosin, prazosin, terazosin, trimazosin and hydralazine.
 33. Theformulation of claim 1, further comprising an additional active agent.34. The formulation of claim 33, wherein the additional active agent isa vasoactive agent.
 35. The formulation of claim 33, wherein theadditional active agent is a smooth muscle relaxant.
 36. The formulationof claim 1, wherein the daily dose of the formulation is in the range ofapproximately 5 mg to 100 mg.
 37. The formulation of claim 36, whereinthe phosphodiesterase inhibitor in the daily dose of the formulation isin a range of approximately 0.1 to 500 mg.
 38. A kit to assist anindividual in administering a drug used for the treatment of erectiledysfunction comprising: a pharmaceutical formulation comprising aselected phosphodiesterase inhibitor; a container for housing thepharmaceutical formulation during storage and prior to use; andinstructions for carrying out drug administration in a manner effectiveto treat erectile dysfunction.
 39. The kit according to claim 38,wherein the pharmaceutical formulation is for buccal administration. 40.The kit according to claim 39, wherein the phosphodiesterase inhibitoris housed in a buccal storage unit with a bioerodible polymeric carrier.41. The kit according to claim 38, further comprising a venous flowcontrol device.
 42. The kit according to claim 41, wherein the venousflow control device comprises a flexible tubing having integralfastening means.